Low-Grade Serous Carcinoma of the Ovary or Peritoneum

David M. Gershenson, MD

The University of Texas MD Anderson Cancer Center

Disclosure

• No disclosures relevant to presentation

M.D. Anderson Grading System for

Ovarian Serous Carcinoma

• Low Grade:– Mild to moderate nuclear atypia

– Mitotic index of up to 12 mitoses/10 HPF (as

secondary feature)

• High Grade:– Marked nuclear atypia

– Mitotic index of > 12 mitoses/10 HPF (as

secondary feature)

Malpica et al

Am J Surg Pathol 2004

MAPK Pathway plays prominent

role in pathogenesis of LGSC

Molecular Biology of LGSC:The Emerging Story

Tumor Subtype BRAF Mutation KRAS Mutation

Serous Tumor LMP 20-40% 40%

LGSC 5% 20-40%

HGSC 0% 0-14%

KRAS G12V Mutation AssociatedWith Worse Prognosis

• KRAS G12V mutation is associated with significantly worse prognosis than KRAS G12D, WT, or variant

• In > 3000 colon cancer cases, of 12 different mutations in KRAS codons, only KRAS G12V was associated with poor OS

• Similar trend in lung cancer study

Tsang et al.J Pathol 2013

RPPA Analysis

Up-regulation of p-Akt

Down-regulation of p-ERK1/2

Down-regulation of Chk1

Combining AKTi (MK2206) is able to suppress the expression of pAKT up-regulated by MEKi (GSK)

Gene Expression Profiling(

Name p-Value

Role of BRCA1 in DNA Damage Response 1.7 E-13

Role of CHK Proteins in Cell Cycle Checkpoint Control 3.00E-08

Hereditary Breast Cancer Signaling 9.20E-08

Mitotic Roles of Polo-Like Kinase 1.47E-07

Cell Cycle Control of Chromosomal Replication 1.52E-07

MEKi down-regulates genes involved in BRCA1 DNA damage response and cell cycle checkpoint control

MEKi interacts with PARPi synergistically

IGF-1 Pathway in

Low-Grade Serous Carcinoma

• Significantly higher

IGF-1 expression in

LGSC vs SBT or

HGSC

• In response to IGF-

1, LGSC cell lines

showed more

intense upregulation

of pAkt than did

HGSC cell lines King et al.Gynecol Oncol 2011

High-Grade

Serous Carcinoma

Low-Grade

Serous Carcinoma

LGSC is Relatively Chemoresistant

Primary Treatment

112 stage II-IV LGSC pts: Primary surgery + chemo

Only 52% NED at completion of primary chemo

Only 5% negative second-look rate

median OS = 82 mos Gershenson et al. Obstet Gynecol 2006

25 advanced stage LGSC pts: Neoadjuvant chemo

Only 1/24 pts had objective response

88% had SD

50% had >50% decrease in CA 125 Schmeler et al. Gynecol Oncol 2007

Low-Grade Serous Tumor Registry

• 350 pts.– 57.3% clinically disease-free at completion of

primary therapy– Median PFS = 28.1 mo.– Median OS = 101.7 mo.

• 287 stage II-IV pts.– Primary surgery + platinum-based chemotherapy– On multivariate analysis, significant factors:

• Presence of tumor at completion of 1° therapy: HR = 1.96• PPC: HR = 0.59• Age > 36 yrs.: HR = 0.44-0.75

Relationship of LGSC to Breast Cancer

287 LGSC Patients Breast Cancer

• Several studies have revealed increased risk of recurrence and death in young (<35 y/o) luminal breast cancer patients

OS 73 vs 103 moP<0.001

Salvage Chemotherapy

• 52 pts received 98 evaluable salvage chemo

regimens

– Platinum-sensitive: 6% RR in 54 patient-

regimens

– Platinum-resistant: 2% RR in 44 patient-

regimens

• SD rate = 62%

– Duration: Median = 22.1 wks (Range, 8-79

wks)

• Median OS = 87.1 mo

• Median TTP = 6.8 mo (Range, 1-54.2 mo)

• 6-mo PFS = 58% Gershenson et al.Gynecol Oncol 2009

Hormonal Therapy = Targeted Therapy

Estrogen Receptor Agents

• Tamoxifen

• Aromatase Inhibitors– Anastrozole

– Letrozole

• GnRH AgonistTherapy– Leuprolide

– Goserelin

• Faslodex

Biomarker Profile of LGSC

• Compared to HGSC, LGSC has lower expression of p53, BCL2, WT1, HER-2/neu, c-KIT, Ki-67, MMP-9

• Compared to HGSC, LGSC has higher expression of ER, PR, ECAD

PR

ER

O-Neill et al.Am J Surg Pathol 2005

Wong et al.Int J Gynecol Pathol 2007

Hormonal Therapy forRecurrent LGSC

• 64 pts received 89 evaluable hormonal regimens

• Response rate = 9% (6 CR, 2 PR)

• Stable disease rate = 66%

– Platinum-sensitive = 83%

– Platinum-resistant = 54%

• Median TTP = 7.4 mos

• 6-mo. PFS = 61%

• ER/PR expression data available in 50 pts

• ER+/PR-: HR = 1.8 compared with ER+/PR+ (P = 0.056)

Gershenson et al.Gynecol Oncol 2012

TypeNo.

monthsPrimary

siteRegimen

(#)Platinum

Status

CA 125 atstart of regimen

CA 125 at end of

regimenER/PR

1 CR 117.6 PP Tamoxifen (4) Sensitive 64 27 Not done

2 CR 112.2 PP Anastrozole (2) Sensitive 99 25 Not done

3 CR 67.9 PP Letrozole (3) Sensitive 52 9 ER+/PR-

4 CR 52.2 PP Letrozole (4) Resistant 109 134 ER+/PR+

5 CR 11.9 Ovary Letrozole (3) Sensitive 12 37 ER+/PR+

6 CR 42.0 PP Letrozole (2) Sensitive 8 6.4 ER+/PR+

7 PR 22.0 Ovary Letrozole (2) Sensitive 13 18.1 ER+/PR+

8 PR 1.63 PP Letrozole (4) Sensitive 13 9.4 Not done

CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; PP = primary peritoneal

Recurrent Low-Grade Serous Carcinoma: Responders to Hormonal Therapy

GOG 0239

• Open label Phase II study

• Eligible– Women with recurrent LGSC of ovary or peritoneum

– Measurable disease

• Biopsy proven

• Prospective pathologic evaluation • Treatment: Selumetinib 50 mg BID

• 1 cycle = 4 weeks

• 52 patients accrued between 17 Dec 2007 – 23 Nov 2009

GOG 239

Outcome

Best Response Current Status

No. Treatment Cycles Acute & Chronic AEs

Mutational Analysis

2/10/2009 6/2/2009

1.8 cm 0.9 cm

Tumor with KRAS mutation

responded to AZD6244

Significant association between pERK proteinexpression and clinical response

GOG 239

BACKGGOG 239ROUND

No correlation between pERK protein expression withBRAF or KRAS mutation status in FFPE specimens

R

GOG 281 Trial Schema

Arm A = Control ArmInvestigators Choice of following:

• Letrozole 2.5 mg po qd continuously• Tamoxifen 20 mg po bid continuously• Paclitaxel 80 mg/m2 IV over 1 hr on day

1 q. 7d, 3 wks on, 1 wk off• Pegylated Liposomal Doxorubicin 40 or

50 mg/m2 IV over 1 hr on day 1 q. 28d• Topotecan 4.0 mg/m2 over 30 min on

days 1, 8 and 15 of a 28 day cycleFor each arm, 1 cycle = 28 days

Arm B = Experimental ArmTrametinib 2 mg po daily

continuous treatmentFor each arm, 1 cycle = 28 days

Crossover to Trametinib

N = 250 patientsPrimary endpoint: PFSSecondary endpoints:• Adverse effects• Objective response• Overall survival• Molecular analyses• Quality of Life

AssessmentsClinical:• At screening day 1 of each

cycle• Following disease

progression, pts will be followed every 12 wk

CT Scans:Screening, then every 8 wkuntil disease progression

Progression

Off Study

ProspectivePathology Review

CT-GuidedFNA/Core Bx

GOG 281

PharmacokineticsProteomics

Plasma Cell-Free DNA Next Generation Sequencing

CT-Guided FNA/Core Bx

Randomized Phase III Trial

NCT01849874

Recurrent LGSC

Physician’s Choice:Paclitaxel

Liposomal DoxorubicinTopotecan

MEK162

Randomized Phase II Trial

NCT01936363

Recurrent LGSC

Pimasertib+

SAR245409

Pimasertib+

Placebo

Randomized Phase II Trial

RTM 1313

Newly Diagnosed Stage II-IV LGSC

Paclitaxel 175 mg/m2

Carboplatin AUC = 6Q. 21 d x 6 cycles

Trametinib 1.5 mg po dailyGSK 214170550 50 mg po daily

Q. 21 d x 6 cycles

Angiogenesis and Low-Grade Serous Carcinoma of the Ovary

• 17 pts treated with bevacizumab

– 10 with ovarian LGSC

– 3 with PPC LGSC

– 4 with SBT

• 15 with bev + chemo and 2 with bev alone

• RR = 40%

• SD = 33%

• 21 pts treated with bevacizumab

• 20 with bev + chemo and 1 with bev alone

• RR = 41%

• SD = 18%

Grisham et al.ASCO 2013

Schmeler et al.ASCO 2010

Key Pathways & Potential Targets:Low-Grade Serous Carcinoma

• MAP Kinase pathway (20-40% KRAS, 5% BRAF)– MEKi, BRAFi

• IGFR-1– AMG 479, BMS-536942, MK-0646

• Angiogenesis pathway– Bevacizumab, Aflibercept, AMG 386, etc.

• PI3K/AKT/mTOR pathway– Everolimus, Temsirolimus, and several others

Future Directions

• Continue to study hormonal therapy and relationship to hormone receptors

• Complete MEKi trials for recurrent LGSC

• Identify biomarkers that predict MEKi activity

• Identify MEKi-independent compensatory pathways

• Develop additional combination targeted agent trials